Additional information

Pharmacokinetics and dosing

A population pharmacokinetic study based on data from 563 individuals (481 men, 82 women), identified factors that contribute to variability in dolutegravir pharmacokinetics. These factors were then used in a model to explore the pharmacokinetic/pharmacodynamic relationship [1]. In the final model, sex was a predictor of bioavailability. Oral bioavailability was 21% (95% CI 13-29%) higher in women than in men [1]. In a simulation based on the model, dolutegravir Cmax, AUC and Cmin were 32%, 26% and 15% higher in women, respectively, but these differences are not considered clinically significant and therefore no dose adjustment will be necessary [1]. Population pharmacokinetic analyses using pooled data from Phase IIb and Phase III adult trials have not shown any clinically relevant sex difference in dolutegravir exposure [2].

Effects

Both men and women have been included in the pivotal studies, although the majority of subjects included have been men (70%-85%) [3, 4]. Data on effect of dolutegravir has not been presented by sex in these studies.

Adverse effects

In a study of adverse effects (AE) of integrase inhibitor-based therapies (in total 1704 patients, of whom 909 men and 70 women were treated with dolutegravir), discontinuation of dolutegravir due to an AE was seen in 6.3% and 15.7% of men and women, respectively [5]. Neuropsychiatric AE leading to discontinuation was reported in 4.6% in men and 10% in women. Relative hazards (RHs) for discontinuation of dolutegravir both due to any AE or neuropsychiatric AEs were higher in women, with a RH of 2.81 (p=0.002) for any AW and a RH of 2.64 (p=0.01) for neuropsychiatric AEs [5].

Another study assessed factors for discontinuing integrase inhibitor therapy in the Swiss HIV Cohort Study. The study population included 4,041 individuals, of whom 1455 men and 495 women were treated with dolutegravir. The only independent risk factor for modifying HIV treatment due to toxicity was female sex (HR 1.98, p<0.001) [6].

Reproductive health issues

Preliminary results from a study of almost 12,000 children born to women with HIV showed a higher risk of neural tube defects among children whose mothers who on dolutegravir-based ART when they became pregnant compared to mothers on other ART (0.9% vs. 0.1%). Until further information is available, EMA advices against dolutegravir treatment in women who are seeking to become pregnant and recommends that women of childbearing age on dolutegravir treatment should use effective contraception [7,8]. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

According to the product information, dolutegravir had no pharmacodynamic effect on luteinizing hormone, follicle stimulating hormone, or progesterone. No dose adjustment of oral contraceptives or dolutegravir is necessary in co-administration [2].